Familial Mediterranean fever (FMF) is an autosomal recessive disease frequently seen in non-Ashkenazi Jews, Arabs, Armenians, and Turks. The main clinical features include periodic attacks of fever and serositis, and amyloidosis in the kidney. The gene mutated in this disease, MEFV, has been cloned and many missense mutations have been identified in affected individuals, in several exons of the gene. MEFV encodes a 3.7 kb transcript that is almost exlusively expressed in granulocytes. The encoded protein, pyrin, is a member of a family of proteins homologous to the Ro52 autoantigen. The function of pyrin is still unclear. It is likely that pyrin plays an important role in the inflammatory and immune response functions of mature granulocytes. In collaboration with Dr. Daniel Kastner, NIAMS, NIH, we are generating mice with either deletions or missense mutations (mimicking those in FMF patients) in the mouse MEFV gene, using standard gene targeting techniques. We have identified the mouse MEFV gene, constructed a gene targeting vector which was introduced into mouse embryonic stem (ES) cells to disrupt the mouse MEFV gene in exon 3. These ES cells have been used to generate mice with this MEFV mutation. So far mice with homozygous MEFV mutations are alive and apparently healthy. More detailed analyses of these mice are underway. - genetics, kidney disease, immunology